Anti-inflammatory agent of benzoyl derivative

ABSTRACT

Anti-inflammatory agent comprises an active ingredient of benzoyl derivative having the formula ##STR1## WHEREIN R 1  represents hydrogen, halogen, hydroxy, C 1-8  alkyl or C 1-8  alkoxy, 
     R 2  represents hydrogen, halogen, hydroxy, vinyl, C 1-8  alkyl or C 1-8  alkoxy, 
     A represents carbonyl, methylene or a single bond, and 
     n is an integer of 1 to 4.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to anti-inflammatory agent which comprises an active ingredient of non-carboxylic benzoyl derivative. 2. Description of the Prior Arts

It has been known to use Aspirine, Oxyphenyl butazone, Indomethacin, Phenyl butazone, Ketophenyl butazone, Azapropazone, Azapropazone, Mephenamic acid, Ibufenac, Benzydamine, Aminophylline as non-steroid anti-inflammatory agent.

These medicines cause side-effects, gastroenteric disorder, headache, etc..

The inventors have studied various compounds and have found that the specific benzoyl compounds which do not belong to classes of the known compounds in chemical formulae had excellent effects as anti-inflammatory agents and analgesics and also had thrombosis inhibiting effect.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide novel type anti-inflammatory agent and anti-thrombosis agent which does not cause side-effect.

Another object of the invention is to produce novel type anti-inflammatory agent.

The objects of the present invention have been attained by providing anti-inflammatory agent which comprises an active ingredient of non-carboxylic benzoyl derivative having the formula ##STR2## wherein R₁ represents hydrogen, halogen, hydroxy, C₁₋₈ alkyl or C₁₋₈ alkoxy,

R₂ represents hydrogen, halogen, hydroxy, vinyl, C₁₋₈ alkyl or C₁₋₈ alkoxy,

A represents carbonyl, methylene or a single bond, and n is an integer of 1 to 4.

It is preferable to be the active ingredient of benzoyl derivative having the formula ##STR3## wherein R'₁ represents hydrogen, halogen or C₁₋₈ alkyl, R'₂ represents a substituent at ortho- or para-position which is hydrogen, C₁₋₈ alkyl or C₁₋₈ alkoxy,

A' represents carbonyl, methylene or a single bond, and n' is an integer of 1 to 3.

It is especially preferable to be the active ingredient of ##STR4## wherein R"₁ represents hydrogen or halogen, and R"₂ represents hydrogen, C₃₋₈ alkyl or C₁₋₈ alkoxy, especially ##STR5##

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The benzoyl derivatives used in the invention do not cause side-effect of gastroenteric disorder and had low toxicity and neutral compounds as different from the conventional ones. For example, the benzoyl derivatives having the formula ##STR6## wherein R₁, R₂, A and n are defined above; are produced by reacting a compound having the formula ##STR7## wherein R₁ and A are defined above and Hal represents a halogen atom with a compound having the formula ##STR8## wherein R₂ and n are defined above, in the presence of a catalyst and when A is --CH₂ --, A can be converted to --CO-- by reacting an oxidizing agent with the product.

The process for producing the benzoyl derivatives will be described in detail.

In the production of the compound I wherein A is a single bond or methylene group, the compound I is produced by reacting the compound II wherein A is a single bond or methylene group with the compound III in the presence of a catalyst.

Suitable catalysts include anhydrous aluminum chloride, anhydrous zinc chloride, anhydrous stannic chloride and other catalysts for these reactions.

Suitable organic solvents such as carbon disulfide, dichloromethane, dichloroethane can be used in the reaction.

The reaction is usually completed at 25 to 75° C. with stirring for 3 to 20 hours.

After the reaction, the solvent is distilled off and water is added to the residue and the product is extracted with benzene and the solution was washed with a caustic alkali solution, and then with water and dried. The solvent is distilled off to obtain a crude object product (ketone). The purification of the product is carried out by a distillation under a reduced pressure or a recrystallization or the other conventional method.

In the production of the compound I wherein A is keto group, the reaction is carried out by using the compound I wherein A is methylene group in the presence of an oxidizing agent such as selenium oxide. In the reaction, suitable solvent such as dioxane, water, ethanol or a mixture thereof can be used. The reaction is usually completed at 110° to 150° C. for 5 to 90 hours.

After the reaction, the precipitate is filtered and the solvent is distilled off under a reduced pressure from the filtrate. Water is added to the residue and the product is extracted with chloroform. The chloroform solution is dried and the solvent is distilled off to obtain the crude object compound (benzyl). The purification can be carried out by the conventional method.

The anti-inflammatory agent of the invention can be applied by various manners such as oral dose, intravenous injection, intramuscular injection and embrocation.

The anti-inflammatory agent of the invention can be used in various forms such as tablet, capsule, injection, syrup, ointment and the other pharmaceutical compositions.

The active ingredients can be applied together with the other anti-inflammatory agent, analgesics, thrombus dissolving agent, thrombus formation inhibiting agent, antibiotics, etc..

The dose of the benzoyl derivative (I) is dependent upon the kinds of the object diseases and is usually 0.5 to 1000 mg/kg/day.

The benzoyl derivatives (I) had various pharmacological effects as shown in the following tablets. As the anti-inflammatory effect, 2-fluorobenzophenone, 4-n-butyl benzophenone, 4-n-butyl-2'-fluorobenzophenone, 4-n-amyl-2-fluorobenzophenone and 2'-fluoro-2,4,6-trimethyl benzophenone have especially high inhibition rate (ED₅₀).

The followings are typical examples of novel compounds of benzoyl derivatives of the invention:

2-Fluoro-4'-n-propyl-benzophenone

2-Fluoro-4'-n-butyl-benzophenone

2-Fluoro-4'-n-amyl-benzophenone

2-Fluoro-4'-methoxy-benzophenone

2-Fluoro-4'-sec. butyl-benzophenone

2-Fluoro-4'-sec.amyl-benzophenone

4-Fluoro-4'-n-butyl-benzophenone

2-Fluoro-2',4',6'-trimethyl-benzophenone

2-Chloro-4'-n-butyl-benzophenone

2-Bromo-4'-n-amyl-benzophenone

2-Bromo-4'-n-octyl-benzophenone

2-Fluoro-4'-iso-propyl-benzophenone

2-Iodo-4'-n-amyl-benzophenone

2-Methyl-4'-n-butyl-benzophenone.

EXAMPLE 1

A 2.8 g (0.02 mole) of benzoic acid chloride was dissolved in 30 ml of carbon disulfide and then, 4.0 g (0.03 mole) of anhydrous aluminum chloride was added to the solution. A 2.68 g (0.02 mole) of n-butyl benzene was further added to the mixture with stirring, and the reaction was carried out at room temperature for 18 hours. Carbon disulfide was distilled off from the reaction mixture and water was added and the reaction product was extracted with benzene. The benzene phase was separated and washed with 1N-NaOH and with water and was dried with anhydrous sodium sulfate. The solvent was distilled off to obtain a pale yellow oily product. The oily product was distilled under a reduced pressure to obtain 4.6 g of 4-n-butyl benzophenone having a boiling point of 184° to 188° C./6 mmHg. (yield of 96.8%).

EXAMPLE 2

A 3.16 g (0.02 mole) of 2-fluoro benzoic acid chloride was dissolved in 30 ml of carbon disulfide and then, 4.0 g (0.03 mole) of anhydrous aluminum chloride was added to the solution. A 2.68 g (0.02 mole) of n-butyl benzene was further added to the mixture with stirring, and the reaction was carried out at room temperature for 18 hours. In accordance with the process of Example 1, the reaction mixture was treated to obtain 3.2 g of 4-n-butyl-2'-fluorobenzophenone having a boiling point of 180° to 190° C./5 mmHg. (yield of 62.5%).

EXAMPLE 3

A 21.4 g (0.16 mole) of n-butyl benzene and 25.0 g (0.162 mole) of phenyl acetic acid chloride were added to 100 ml of carbon disulfide, and 22.0 g (0.165 mole) of anhydrous aluminum chloride was further added to them with stirring and the reaction was carried out at room temperature for 15 hours.

In accordance with the process of Example 1, the reaction mixture was treated and the product was recrystallized from ethanol to obtain 39.0 g of 4-n-butyl-α-phenyl acetophenone having a melting point of 53° to 55° C. which had the formula ##STR9##

EXAMPLE 4

A 19.7 g (0.78 mole) of 4-n-butyl-α-phenyl acetophenone of Example 3 was dissolved in 200 ml of a mixture of dioxane 5; water 1, and 9.0 g (0.81 mole) of selenium dioxide was added to the solution and the mixture was heated under refluxing to react them for 90 hours. The resulting black precipitate was filtered off and the solvent was distilled off under a reduced pressure from the filtrate. The residue was dissolved in chloroform and the solution was washed with water and was dried. The solvent was distilled off under a reduced pressure and the resulting oily product was distilled under a reduced pressure to obtain 18.7 g of 4-n-butyl benzyl having a boiling point of 240° to 242° C./5 mmHg which had the formula ##STR10##

EXAMPLE 5

A 3.17 g (0.02 mole) of 2-fluorobenzoic acid chloride was dissolved in 30 ml of carbon bisulfide and then, 3.99 g (0.03 mole) of anhydrous aluminum chloride was added to the solution. A 2.68 g (0.02 mole) of sec-butyl benzene was further added to the mixture with stirring and the reaction was carried out at room temperature for 18 hours. Carbon bisulfide was distilled off from the reaction mixture and water was added and the reaction product was extracted with benzene. The benzene phase was separated washed with 1N-NaOH and with water and was dried with anhydrous sodium sulfate. The solvent was distilled off to obtain a pale yellow oily product. The oily product was distilled under a reduced pressure to obtain 3.9 g of 4-sec-butyl-2'-fluorobenzophenone having a boiling point of 152° to 160° C./5 mmHg. (yield of 76.4%).

EXAMPLE 6

A 3.17 g (0.02 mole) of 2-fluorobenzoic acid chloride was dissolved in 30 ml of carbon disulfide and then, 3.99 g (0.03 mole) of anhydrous aluminium chloride was added to the solution. A 2.96 g (0.02 mole) of sec-amyl benzene was further added to the mixture with stirring, and the reaction was carried out at room temperature for 18 hours.

In accordance with the process of Example 1, the reaction mixture was treated to obtain 4.0 g of 4-sec-amyl-2'-fluorobenzophenone having a boiling point of 150 to 157° C./4 mmHg. (yield of 74%).

The properties of the compounds produced in Examples 1 to 6 and the other compounds produced by the same manner are shown. The physical properties are shown in Table 1 and the pharmacological effects are shown in Table 2.

In the column for melting points and boiling points in Table 1, the symbol * means the melting point. In the column for IR in Table 1, the symbol * means ν_(max) ^(nujol) cm⁻ 1. In Table 2, the pharmacological effects and toxicity were measured by the following tests.

Anti-inflammatory effect

The edema inhibition rates (%) of the samples of the invention were measured in accordance with acute carragheenin edema method described in Nippon Yakurigaku Zatsushi Vol. 56, Page 575 in 1960.

The edema was induced by subcutaneous injection of 1% carraheenin suspension in saline to the hind paws of male rats weighing 150 to 180 g. Each sample was orally given at the dosage of 100 mg/kg just before the inoculation of carragheenin.

In Table 2, the values shown in brackets show the 50% inhibition rate ED₅₀ (mg/kg).

Analgesic effect

In accordance with the method described in Federation Proceedings Vol. 18, Page 412 in 1959, percentage diminition of times of painful stretchings (%) following the intraperitorineal injection of 0.7% acetic acid solution in male mice (weight of 20 to 25 g) were counted.

Each sample was orally administrated in the dosage of 100 mg/kg before injection of acetic acid.

Blood platelet aggregation inhibiting effect

Male rabbits (Japan original white strain 3.3 to 3.6 kg) were anesthetized with Thiopental sodium and blood was sampled from the carotid artery. In order to prevent coaggulation of the blood, 10% by volume of 3.8% sodium citrate aqueous solution was added to the blood.

The light transmittances were adjusted to 0% with PRP (supernatant platelet rich plasma separated by centrifugation at 1600 rpm from blood) and to 100% with PPP (supernatant platelet poor plasma separated by centrifugation at 3000 rpm from blood) by using the Blood platelet aggregometer (Model EEl-169, Electroserum Co. England). The platelet aggregation was measured in accordance with the test method described in Federation Proceedings Vol. 26, Page 115 in 1967, using collagen as an aggregation inducer.

The percentage inhibition of platelet aggregation was given as the difference in the platelet aggregation rate % between the sample (concentration: 10⁻⁴ mole) and control (saline), with the rate of control adjusted to 100%.

Acute toxicity

Each sample was dissolved in olive oil or dispersed in 1% Tween 20 aqueous solution. The test was carried out by the oral dose in male mice having a weight of 22 to 25 g.

Ten animals were used at each of three or more dosage levels. General appearances and behaviors were observed for 7 days after treatment, and LD₅₀ was calculated on the basis of mice that succumbed within 72 hours using Van Der Warden method.

Inhibiting effect on thrombosis:

The inhibiting effects of the samples of the invention on thrombosis were tested by the following test method.

SD type male rats (360 to 580 g) were anesthetized by the intraperitoneal injection of Thiopental sodium (67 mg/kg). In accordance with the technique described in Proceeding Society of Experimental Biological Medicine Vol. 139, Pages 548 to 552 in 1972 by Hermann, the by-pass was formed between the left juglar vein and the right carotid artery with a polyethylene tube.

A 0.5 ml of 50 μ/ml of the heparin physiological saline was added through the polyethylene tube before the first blood circulation. After the blood circulation for 15 minutes, the circulation was stopped in the middle of the tubing at artery side with a pinch cock.

Then, 0.2 ml of the heparin physiological saline was added to remove the blood coagulates on the tubing wall and another new polyethylene tubing filled with the heparin solution and containing a piece of new silk thread was attached between the venous and artery tubing ends.

The blood circulation was reestablished by opening the pinch cock. After 15 minutes, the wet weight of thrombus on the silk thread was similarly measured. In the same manner, the third circulation was performed and wet weight of thrombus measured.

The amount of thrombus was given by the equation A. ##EQU1## Each sample was suspended in an aqueous solution of sodium carboxymethyl cellulose and the oral dose of the suspension (100 mg/kg) was performed at 5 hours before the first blood circulation. The amount of thrombus after the oral dose of the sample was calculated in the same manner as that of control circulations.

The thrombosis inhibition rate was given by the equation B. ##EQU2## The test results are shown in Table 2.

    ______________________________________                                         Composition 1:                                                                 ______________________________________                                         Active ingredient No. 8  100 g                                                 Fine powdery silica                                                            (Solider 101)            100 g                                                 Crystalline cellulose    645 g                                                 Corn starch              125 g                                                 Magnesium stearate        30 g                                                 ______________________________________                                    

The fine powdery silica was admixed with the same amount of the active ingredient No. 8, and the mixture was passed through a 32 mesh sieve. The mixture was admixed with crystalline cellulose, corn starch and magnesium stearate and the components were uniformly mixed by passing through a 32 mesh sieve. The mixture was treated by the tablet machine to form tablets having a diameter of 8 mm and a weight of 200 mg.

    ______________________________________                                         Composition 2:                                                                 ______________________________________                                         Active ingredient No. 3  125 g                                                 Lactose                  650 g                                                 Crystalline cellulose    100 g                                                 Corn starch              100 g                                                 3% hydroxypropyl                                                               cellulose aqueous solution                                                                              500 ml                                                Magnesium stearate       10 g                                                  ______________________________________                                    

The lactose, crystalline cellulose and corn starch were admixed with the active ingredient No. 3, and the mixture was passed through a 60 mesh sieve to uniformly mix the components. The mixture was charged in a kneader and 3% hydroxypropyl cellulose aqueous solution was added and the mixture was kneaded. The mixture was granulated by passing through a 16 mesh sieve and was dried at 50° C. and then passed through a 16 mesh sieve to cause uniform particle sizes. The granules were mixed with magnesium stearate and was treated by the tablet machine to form tablets having a diameter of 8 mm and a weight of 200 mg.

    ______________________________________                                         Composition 3:                                                                 ______________________________________                                         Active ingredient No. 119                                                                               100 g                                                 Fine powdery silica      100 g                                                 (Solider 101)                                                                  Crystalline cellulose    645 g                                                 Corn starch              125 g                                                 Magnesium stearate        30 g                                                 ______________________________________                                    

The fine powdery silica was admixed with the same amount of the active ingredient No. 119 and the mixture was passed through a 32 mesh sieve. The mixture was admixed with crystalline cellulose, corn starch and magnesium stearate and the components were uniformly mixed by passing through a 32 mesh sieve. The mixture was treated by the tablet machine to form tablets having a diameter of 8 mm and a weight of 200 mg.

    ______________________________________                                         Composition 4:                                                                 ______________________________________                                         Active ingredient No. 136                                                                               125 g                                                 Lactose                  650 g                                                 Crystalline cellulose    100 g                                                 Corn starch              100 g                                                 3% hydroxypropyl cellulose                                                     aqueous solution         500 ml                                                Magnesium stearate        10 g                                                 ______________________________________                                    

The active ingredient No. 136 was uniformly mixed with lactose, crystalline cellulose and corn starch by passing through a 60 mesh sieve. The 3% hydroxypropyl cellulose aqueous solution was added to the mixture in a kneader and the mixture was granulated by passing through a 16 mesh sieve and was dried at 50° C. under air-flow. The dried granules were passed through a 16 mesh sieve to cause uniform particle sizes. The granules were mixed with magnesium stearate and was treated by the tablet machine to form tablets having a diameter of 8 mm and a weight of 200 mg.

                                      Table 1                                      __________________________________________________________________________                            Boiling Point                                           Active                 (° C/mmHg)                                       ingre-                 or       IR                                             dient                  melting  (CO)                                           No. R.sub.1                                                                              R.sub.2  A   point (° C)                                                                      ν .sub.max.sup.nujol cm.sup.-1              __________________________________________________________________________                                     1                                              1   2 - CH.sub.3                                                                         2,4-diCH.sub.3                                                                          single                                                                             155˜160/3                                                                         1660                                                              bond                                                        2   "     2,5-diCH.sub.3                                                                          "   148˜152/3                                                                         1655                                           3   "     2,4,6-triCH.sub.3                                                                       "   111˜112*                                                                          1660*                                          4   4-n-C.sub.6 H.sub.13                                                                 2,4-diCH.sub.3                                                                          "   203˜5/4                                                                           1655                                           5   "     4-n-C.sub.4 H.sub.9                                                                     "   228/3    1650                                           6   "     4-n-C.sub.3 H.sub.7                                                                     "   213˜5/3                                                                           1650                                           7   2-F   "        "   160˜5/5                                                                           1660                                           8   "     4-n-C.sub.4 H.sub.9                                                                     "   180˜190/5                                                                         1660                                           9   "     4-n-C.sub.5 H.sub.11                                                                    "   190˜5/5                                                                           1660                                           10  "     2,4-diCH.sub.3                                                                          "   150˜5/5                                                                           1655                                           11  "     2,4,6-triCH.sub.3                                                                       "   155˜160/5                                                                         1660                                           12  H     4-OCH.sub.3                                                                             CO  180˜190/2                                                                         1660                                           13  "     2,4,6-triC.sub.2 H.sub.5                                                                single                                                                             176.5˜178/6.5                                                                     1665                                                              bond                                                        14  4-Cl  2,4,6-triCH.sub.3                                                                       "   65˜7*                                                                             1660*                                          15  H     2-F      "   190/29   1665                                           16  "     2,5-n-diC.sub.3 H.sub.7                                                                 "   172˜182/5                                                                         1665                                           17  4-CH.sub.3                                                                           2,5-n-diC.sub.4 H.sub.9                                                                 "   175˜191/2.5                                                                       1660                                           18  4-OCH.sub.3                                                                          4-n-C.sub.4 H.sub.9                                                                     "            1645                                           19  H     "        "   184˜188/6                                                                         1660                                           20  "     4-n-C.sub.3 H.sub.7                                                                     "   161˜167/3.5                                                                       1660                                           21  "     4-i-C.sub.3 H.sub.7                                                                     "   143˜4/2                                                                           1660                                           22  "     4-t-C.sub.4 H.sub.9                                                                     "   141˜144/1                                                                         1660                                           23  "     4-n-C.sub.5 H.sub.11                                                                    "   164˜167/2.5˜3                                                               1660                                           24  "     4-n-C.sub.6 H.sub.13                                                                    "   185˜190/3                                                                         1655                                           25  "     4-n-C.sub.7 H.sub.15                                                                    "   173˜175/2˜2.5                                                               1660                                           26  "     4-n-C.sub.8 H.sub.17                                                                    "   185˜190/3                                                                         1655                                           27  "     H        "   48˜49.5*                                                                          1660*                                          28  "     4-OCH.sub.3                                                                             "   58˜60*                                                                            1660                                           29  "     4-n-C.sub.4 H.sub.9                                                                     CO  240˜242/5                                                                         1660                                           30  "     2,4,6-triCH.sub.3                                                                       single                                                                             131˜133/1.5˜2                                                               1665                                                              bond                                                        31  "     2,3,4-triCH.sub.3                                                                       "   145.5˜148/2                                                                       1665                                           32  "     2,4,5-triCH.sub.3                                                                       "   152˜154/3                                                                         1665                                           33  4-CH.sub.3                                                                           4-C.sub.2 H.sub.5                                                                       "   46˜9*                                                                             1645*                                          34  "     4-n-C.sub.3 H.sub.7                                                                     "   160˜3/3                                                                           1650                                           35  "     4-n-C.sub.4 H.sub.9                                                                     "   160˜5/3                                                                           1655                                           36  "     4-n-C.sub.6 H.sub.13                                                                    "   190˜6/2                                                                           1650                                           37  H     2,4-diCH.sub.3                                                                          "   120˜122/1˜1.5                                                               1660                                           38  "     2,5-diCH.sub.3                                                                          "   132˜134.5/3                                                                       1665                                           39  "     4-n-C.sub.4 H.sub.9                                                                     CH.sub.2                                                                           53˜55*                                                                            1670*                                          40  2-CH.sub.3                                                                           "        single                                                                             157˜163/2                                                                         1665                                                              bond                                                        41  "     4-n-C.sub.5 H.sub.11                                                                    "   159˜169/1                                                                         1665                                           42  H     4-n-OC.sub.4 H.sub.9                                                                    "   27˜29*                                                                            1650*                                          43  4-n-C.sub.4 H.sub.9                                                                  4-n-C.sub.4 H.sub.9                                                                     "   205˜210/3.5                                                                       1650                                           44  2-Cl  4-n-C.sub.4 H.sub.9                                                                     "   200˜5/5                                                                           1660                                           45  4-OCH.sub.3                                                                          4-n-C.sub.5 H.sub.11                                                                    "            1645                                           46  4-n-C.sub.4 H.sub.9                                                                  4-F,2-CH.sub.3                                                                          "   140˜142/3                                                                         1650                                           47  H     H        CH.sub.2                                                                           55*      1670*                                          48  "     4-CH.sub.3                                                                              "   104˜106*                                                                          1670*                                          49  "     4-n-C.sub.3 H.sub.7                                                                     "   53-54*   1670*                                          50  "     4-n-C.sub.10 H.sub.21                                                                   "   50-52*   1670*                                          51  "     4-n-C.sub.11 H.sub.23                                                                   "   51-53*   1670*                                          52  "     4-n-C.sub.12 H.sub.25                                                                   "   55-58*   1670*                                          53  "     H        CO  95*      1660*                                          54  "     4-CH.sub.3                                                                              "   180/1    1660                                           55  "     4-C.sub.2 H.sub.5                                                                       "   170/1    1660                                           56  "     4-n-C.sub.6 H.sub.13                                                                    "   200-210/1                                                                               1660                                           57  "     4-OCH.sub.3                                                                             CH.sub.2                                                                           66-68*   1660*                                          58  "     4-n-OC.sub.3 H.sub.7                                                                    "   85-87*   1670*                                          59  "     4-n-OC.sub.5 H.sub.11                                                                   "   62-65*   1675*                                          60  4-Cl  4-OCH.sub.3                                                                             "   118-119* 1630*                                          61  "     4-n-OC.sub.4 H.sub.9                                                                    "   100-101* 1630*                                          62  "     4-n-OC.sub.6 H.sub.13                                                                   "   88-89*   1630*                                          63  "     4-n-C.sub.3 H.sub.7                                                                     single                                                                             77-78*   1640*                                                             bond                                                        64  "     4-n-C.sub.4 H.sub.9                                                                     "   62-63*   1640*                                          65  H     4-CH.sub.3                                                                              "   45-47*   1640*                                          66  "     4-C.sub.2 H.sub.5                                                                       "   133-134/2                                                                               1655                                           67  "     4-i-C.sub.4 H.sub.9                                                                     "   170-172/4                                                                               1655                                           68  "     4-n-C.sub.10 H.sub.21                                                                   "   205-210/2                                                                               1660                                           69  "     4-n-C.sub.12 H.sub.25                                                                   "   215-219/2                                                                               1660                                           70  "     4-n-C.sub.9 H.sub.19                                                                    "   187-194/25-3                                                                            1665                                           71  "     4-n-C.sub.11 H.sub.23                                                                   "   199-209/2.5                                                                             1660                                           72  "     3,4-diCH.sub.3                                                                          "   139-144/1                                                                               1660                                           73  "     4-cycloC.sub.6 H.sub.13                                                                 "   170-182/1                                                                               1660                                           74  "     2,4-diOCH.sub.3                                                                         "   87-88*   1660*                                          75  "     2,5-diOCH.sub.3                                                                         "   50-52*   1660*                                          76  "     2,4,6-triOCH.sub.3                                                                      "   178-179* 1660*                                          77  "     2,5-di-n-C.sub.4 H.sub.9                                                                "   158-169/2                                                                               1660                                           78  "     2,3,5,6-tetraCH.sub.3                                                                   "   116-118* 1670*                                          79  "     2,3,4,6-tetraCH.sub.3                                                                   "   171-172/5.5                                                                             1670                                           80  "     2,5-diC.sub.2 H.sub.5                                                                   "   161-165/4                                                                               1665                                           81  "     4-OC.sub.2 H.sub.5                                                                      "   38-39*   1645*                                          82  "     4-CHCH.sub.2                                                                            "   oily     1660                                           83  4-CH.sub.3                                                                           4-CH.sub.3                                                                              "   91-93*   1645*                                          84  "     4-n-C.sub.5 H.sub.11                                                                    "   170-175/2                                                                               1655                                           85  "     4-n-C.sub.7 H.sub.15                                                                    "   195-203/3                                                                               1650                                           86  "     2,4,6-tri CH.sub.3                                                                      "   148-149/2.5                                                                             1665                                           87  3-CH.sub.3                                                                           4-n-C.sub.3 H.sub.7                                                                     "   162-165/4                                                                               1650                                           88  "     4-n-C.sub.4 H.sub.9                                                                     "   165-170/3                                                                               1650                                           89  "     4-n-C.sub.5 H.sub.11                                                                    "   175-180/3                                                                               1650                                           90  2-CH.sub.3                                                                           4-n-C.sub.3 H.sub.7                                                                     "   140-147/1.5                                                                             1665                                           91  "     2,3,5,6-tetraCH.sub.3                                                                   "   105-107* 1660*                                          92  4-OCH.sub.3                                                                          4-OCH.sub.3                                                                             "   141-142* 1640*                                          93  "     4-n-C.sub.3 H.sub.7                                                                     "   oily     1645                                           94  4-n-OC.sub.4 H.sub.9                                                                 2,4,6-triCH.sub.3                                                                       "   190-194/3                                                                               1660                                           95  "     4-n-C.sub.4 H.sub.9                                                                     "   190-210/3                                                                               1650                                           96  4-n-C.sub.3 H.sub.7                                                                  2,4-diCH.sub.3                                                                          "   185/4    1655                                           97  "     2,4,6-triCH.sub.3                                                                       "   183-185/4                                                                               1650                                           98  "     4-n-C.sub.4 H.sub.9                                                                     "   207-210/3.5                                                                             1655                                           99  "     4-n-C.sub.5 H.sub.11                                                                    "   217-220/4                                                                               1650                                           100 4-n-C.sub.4 H.sub.9                                                                  4-n-C.sub.7 H.sub.15                                                                    "   oily     1650                                           101 "     4-n-C.sub.8 H.sub.17                                                                    "    "       1650                                           102 "     4-n-C.sub.9 H.sub.19                                                                    "    "       1650                                           103 4-n-C.sub.6 H.sub.13                                                                 2,4,6-triCH.sub.3                                                                       "   205-210/4                                                                               1660                                           104 4-OH  4-n-C.sub.3 H.sub.7                                                                     "            1630                                           105 "     4-n-C.sub.5 H.sub.11                                                                    "            1630                                           106 4-C.sub.2 H.sub.5                                                                    4-C.sub.2 H.sub.5                                                                       "   47*      1650*                                          107 4-OCH.sub.3                                                                          4-C.sub.2 H.sub.5                                                                       "   41-43*   1640*                                          108 4-OH  2,4,6-triCH.sub.3                                                                       "            1630                                           109 H     4-OH     "   132-135* 1630*                                          110 4-n-C.sub.3 H.sub.7                                                                  4-n-C.sub.3 H.sub.7                                                                     "   65-67*   1650*                                          111 4-n-C.sub.5 H.sub.11                                                                 4-n-C.sub.5 H.sub.11                                                                    "   220-222/4                                                                               1650                                           112 4-n-C.sub.2 H.sub.5                                                                  4-n-C.sub.3 H.sub.7                                                                     "            1660                                           113 H                                                                                     ##STR11##                                                                              "   146-147* 1660*                                          114 4-F   4-F      "   102-105* 1640*                                          115 2-Cl  4-F      "   60-62*   1660*                                          116 2-F   4-OCH.sub.3                                                                             "   155-160/5                                                                               1660                                           117 "     4-i-C.sub.3 H.sub.7                                                                     "   142-152/5                                                                               1655                                           118 "     4-i-C.sub.4 H.sub.9                                                                     "   152-7/4  1660                                           119 "     4-s-C.sub.4 H.sub.9                                                                     "   152-160/5                                                                               1660                                           120 "     4-t-C.sub.4 H.sub.9                                                                     "   152-157/5                                                                               1660                                           121 "     4-s-C.sub.5 H.sub.11                                                                    "   150-7/4  1655                                           122 "     4-t-C.sub.5 H.sub.11                                                                    "   160-5/5  1665                                           123 3-F   4-n-C.sub.4 H.sub.9                                                                     "   182-7/5  1660                                           124 "     4-n-C.sub.5 H.sub.11                                                                    "   185-195/5                                                                               1655                                           125 "     2,4,6-triCH.sub.3                                                                       "   oily     1670                                           126 "     2,4-di-CH.sub.3                                                                         "   150-3/5  1660                                           127 4-F   4-n-C.sub.4 H.sub.9                                                                     "   39-40*   1645*                                          128 "     4-n-C.sub.5 H.sub.11                                                                    "   46-7*    1645*                                          129 "     4-n-C.sub.8 H.sub.17                                                                    "   32-3*    1645*                                          130 "     2,4-diCH.sub.3                                                                          "   149-152/5                                                                               1660                                           131 "     2,4,6-triCH.sub.3                                                                       "   150-2/5  1670                                           132 2-Cl  4-n-C.sub.3 H.sub.7                                                                     "   188-190/5                                                                               1660                                           133 "     4-n-C.sub.5 H.sub.11                                                                    "   200-4/5  1665                                           134 "     4-n-C.sub.8 H.sub.17                                                                    "   235-7/5  1665                                           135 "     2,4-diCH.sub.3                                                                          "   174-6/5  1660                                           136 4-Cl  4-OCH.sub.3                                                                             "   118-9*   1630.sup.N*                                    137 "     4-OC.sub.4 H.sub.9                                                                      "   100-1*   1630.sup.N*                                    138 "     4-OC.sub.6 H.sub.13                                                                     "   88-9*    1630.sup.N*                                    139 3-Cl  4-n-C.sub.3 H.sub.7                                                                     "   27-8*    1670*                                          140 "     4-n-C.sub.5 H.sub.11                                                                    "   355-7*   1660*                                          141 "     4-n-C.sub.8 H.sub.17                                                                    "   oily     1660                                           142 2-Br  4-n-C.sub.3 H.sub.7                                                                     "   39-40*   1670*                                          143 "     4-n-C.sub.4 H.sub.9                                                                     "   203-210/5                                                                               1660                                           144 "     4-n-C.sub.5 H.sub.11                                                                    "   210-215/5                                                                               1670                                           145 "     4-n-C.sub.8 H.sub.17                                                                    "   240-3/4  1665                                           146 "     2,4-diCH.sub.3                                                                          "   182-3/5  1660                                           147 "     2,4,6-triCH.sub.3                                                                       "   113-4*   1670*                                          148 3-Br  4-n-C.sub.8 H.sub.17                                                                    "   240-5/6  1650                                           149 "     2,4-diCH.sub.3                                                                          "   180-2/6  1650                                           150 4-Br  4-n-C.sub.3 H.sub.7                                                                     "   93-4*    1640*                                          151 "     4-n-C.sub.8 H.sub.17                                                                    "   53-4*    1640*                                          152 "     2,4-diCH.sub.3                                                                          "   180-5/6  1655                                           153 "     2,4,6-triCH.sub.3                                                                       "   70-1*    1660*                                          154 2-I   4-n-C.sub.3 H.sub.7                                                                     "   190-7/5  1660                                           155 "     4-n-C.sub.4 H.sub.9                                                                     "   202-9/4  1660                                           156 "     4-n-C.sub.5 H.sub.11                                                                    "   207-218/4                                                                               1660                                           157 "     4-n-C.sub.8 H.sub.17                                                                    "   215-220/4                                                                               1665                                           158 "     2,4-diCH.sub.3                                                                          "   192-7/5  1660                                           159 "     2,4,6-triCH.sub.3                                                                       "   97-8*    1665*                                          160 3-I   4-n-C.sub.4 H.sub.9                                                                     "   45-7*    1645*                                          161 "     4-n-C.sub.8 H.sub.17                                                                    "   215-20/4 1655                                           162 "     2,4-diCH.sub.3                                                                          "   74-5*    1655*                                          163 "     2,4,6-triCH.sub.3                                                                       "   85-6*    1660*                                          164 4-I   4-n-C.sub.8 H.sub.17                                                                    "   64-5*    1640*                                          165 "     2,4-diCH.sub.3                                                                          "   200-5/7  1655                                           166 "     2,4,6-triCH.sub.3                                                                       "   72-3*    1665*                                          __________________________________________________________________________

                  table 2                                                          ______________________________________                                         Active                          Acute                                          ingre-                    Blood toxicity                                                                              Thrombo-                                dient Anti-inf. Analgesic platelet                                                                             LD.sub.50                                                                             sis inh.                                No.   (%)       (%)       agg. inh.                                                                            (mg/kg)                                                                               (%)                                     ______________________________________                                         1     36.2 (700)                                                                               10.2      21.7  1000   28.5                                    2     36.8      13.5      19.5  1000   30.3                                    3     40.0 (290)                                                                               11.3      17.3  1500   38.3                                    4     44.2      16.3      20.5  4000   15.9                                    5     46.3      12.1      15.3  5000   20.3                                    6     44.2      14.5      17.8  5000   15.9                                    7     55.6(78)  15.0      23.0  1500   24.6                                    8     82.6(38)  14.8      24.0  1500   38.0                                    9     74.6(22)  15.3      14.6  3000   25.3                                    10    47.5(90)  20.3      18.5  500    29.7                                    11    62.3(22)  13.9      16.5  500    42.9                                    12    43.9      10.2      20.1  10000  18.3                                    13    38.9(>400)                                                                               15.8      14.3  2000   20.5                                    14    37.3(130) 19.2      18.1  500    23.3                                    15    61.4(65)  18.5      23.2  4000   26.5                                    16    45.2(140) 12.4      8.6   1500   21.5                                    17    36.3(180) 10.3      17.3  2000   19.5                                    18    41.6      20.1      9.3   2000   24.2                                    19    63.4(25)  30.1      18.6  2400   7.9                                     20    42.7      17.3      36.6  2000   4.1                                     21    37.3      16.1      8.6   2000   5.4                                     22    36.4      8.2       9.5   2000   7.9                                     23    50.4      10.1      13.8  5000   22.3                                    24    37.6      47.7      10.5  6000   24.3                                    25    40.8      48.6      7.8   8000   22.1                                    26    47.2      35.9      3.1   10000  24.8                                    27    47.7(120) 13.2      25.7  3700   25.9                                    28    44.1      4.2       20.4  >10000 7.3                                     29    44.7(130) 2.7       11.1  10000  15.3                                    30    64.7(45)  13.4      8.7   1500   44.8                                    31    35.4      9.5       18.2  1500   23.5                                    32    47.7      26.2      12.4  2000   25.0                                    33    43.9      15.5      20.5  3000   28.3                                    34    43.1      12.1      16.4  5000   24.5                                    35    48.5      17.8      11.3  >10000 26.5                                    36    34.8      13.7      15.1  >10000 28.1                                    37    39.6      9.8       17.4  1000   5.3                                     38    37.5(170) 18.0      20.9  1000   8.3                                     39    35.9      23.1      2.6   >10000 15.9                                    40    58.1(120) 20.3      11.9  2000   30.3                                    41    47.4      14.6      14.4  3000   28.5                                    42    35.8      26.8      4.4   3000   10.7                                    43    34.0      0         3.5   >10000 86                                      44    57.7(70)  15.6      10.5  2000   35.6                                    45    37.8(>400)                                                                               12.5      17.7  5000   30.8                                    46    43.4(400) 13.4      16.5  2000   34.5                                    47    20.9      13.1      18.3         15.6                                    48    26.0      12.5      20.5         18.3                                    49    10.7      18.2      28.5  8000   13.4                                    50    25.5      16.4      8.7   >10000 28.3                                    51    24.6      18.3      9.5          13.5                                    52    25.5      12.5      6.8          10.1                                    53    20.3      14.2      10.1         19.2                                    54    25.5      11.3      15.4         20.3                                    55    29.0      15.8      23.3         16.4                                    56    14.9      20.5      20.3  10000  15.1                                    57    16.1      10.3      12.5         6.5                                     58    15.3      19.8      20.1         14.6                                    59    20.7      22.8      25.6         14.1                                    60    13.2      6.3       4.0          12.3                                    61    16.7      15.1      15.8         8.5                                     62    12.5      10.2      12.3         7.8                                     63    11.8      8.2       15.6         6.2                                     64    21.4      6.6       28.5  3000   15.9                                    65    17.3      10.9      21.0         19.2                                    66    34.4      15.7      20.7  2000   20.5                                    67    20.0      19.1      18.5  2000   17.3                                    68    17.6      5.8       16.5         20.3                                    69    12.0      6.7       13.5         12.7                                    70    23.2      7.0       17.2         10.0                                    71    20.0      9.2       19.5         11.4                                    72    29.9      23.4      28.7  1000   30.2                                    73    32.1      10.0      20.3  6000   28.8                                    74    30.2      24.2      18.5  5000   28.9                                    75    29.5      22.0      30.7  5000   29.2                                    76    15.7      13.9      16.2  2500   18.4                                    77    13.2      10.8      25.1         17.5                                    78    12.5      5.4       19.9         20.2                                    79    33.2      20.8      26.8  1000   31.5                                    80    31.9      16.2      30.3         28.5                                    81    15.3      17.6      18.3         20.3                                    82    23.8      13.5      20.5         30.1                                    83    20.0      12.1      27.6         19.3                                    84    28.4      15.3      8.6   10000  16.0                                    85    18.7      10.2      18.7         16.2                                    86    17.7      8.3       28.3         35.6                                    87    18.7      11.2      30.1         25.8                                    88    21.6      5.6       24.5         29.3                                    89    27.6      4.3       22.6  10000  13.2                                    90    19.7      13.7      10.8         15.0                                    91    21.4      15.2      14.7         31.0                                    92    10.0      11.1      8.9          20.3                                    93    20.4      14.7      24.4         26.8                                    94    26.6      15.8      27.9  500    37.4                                    95    17.1      14.5      30.0         32.3                                    96    26.1      18.9      28.5         36.7                                    97    13.0      14.7      26.8         37.3                                    98    31.9      16.4      28.3  4000   35.4                                    99    34.1      15.5      29.5  5000   30.3                                    100   14.0      10.0      22.4         27.6                                    101   23.1      18.3      27.9         31.4                                    102   22.4      15.2      30.4         29.7                                    103   29.7      14.2      29.5  500    35.8                                    104   27.4      13.2      25.3  3000   30.5                                    105   33.6      14.1      24.1  4000   31.4                                    106   26.4      7.3       20.3  1000   20.2                                    107   20.3      13.2      20.3         19.6                                    108   10.5      3.1       28.4         34.7                                    109   12.7      2.6       13.7         20.3                                    110   17.0      10.5      20.5         18.6                                    111   20.6      11.3      10.3         17.3                                    112   14.1      6.7       11.8         15.5                                    113   38.7      14.5      25.8  4000   30.4                                    114   33.2      18.3      26.8  2000   31.1                                    115   14.5      11.8      25.4         27.5                                    ______________________________________                                    

                  Table 2'                                                         ______________________________________                                         Active                                                                         ingredient                 Acute                                               No.          Anti-inf.     toxicity                                            ______________________________________                                         116          59.8          4000                                                117          53.3          1500                                                118          32.7          2000                                                119          60.7          2000                                                120          38.3          750                                                 121          64.5          3000                                                122          39.3          2000                                                123          38.3          1500                                                124          23.5          3000                                                125          18.1          1000                                                126          27.7          1000                                                127          58.8          5000                                                128          33.6          4000                                                129          38.6          >10000                                              130          37.8          2000                                                131          33.6          2000                                                132          14.9          2000                                                133          38.3          2000                                                134          35.1          3000                                                135          37.2          1000                                                136          13.2          2000                                                137          16.7          2000                                                138          12.5          2500                                                139          11.7          1000                                                140          14.9          1000                                                141          13.8          2000                                                142          38.9          1500                                                143          45.4          1500                                                144          50.0          1500                                                145          60.2          2000                                                146          23.1          1000                                                147          20.4          1000                                                148          36.3          2000                                                149          42.2          500                                                 150          14.0          2000                                                151          15.3          2500                                                152          22.6          1500                                                153          27.8          1500                                                154          29.0          >10000                                              155          31.8          >10000                                              156          43.0          >10000                                              157          37.4          >10000                                              158          32.7          2000                                                159          15.9          1000                                                160          10.8          2500                                                161          20.9          5000                                                162          13.0          1500                                                163          16.4          1500                                                164          29.0          >10000                                              165          19.2          5000                                                166          21.5          5000                                                ______________________________________                                    

Chronic Inflammation (Adjuvant-Induced Arthritis)

The effects of (1) 4-n-butyl benzophenone and (2) 4-n-butyl-2'-fluorobenzophenone against adjuvant-induced arthritis were studied.

For the study, adult female rats of Sprague Drawley strain weighing approximately 200g were used. All rats received 0.1 ml of a suspension of dry heat-killed tubercle bacilli (human strains, commercial product of Difco Co.) in liquid paraffin (5 mg/ml, w/v) by a single intradermal injection into the tail.

The treatment of the animals by the test compounds were started fourteen days after injection of the adjuvant when arthritis developed sufficiently accompanying edema and erythema in paws. Each compound was orally given to animals daily for ten days. Dosage levels employed were 50 and 100 mg/kg/day. Phenylbutazone was used as the reference drug.

Evaluations were made using the following parameters.

(1) Body weight gain

(2) Relative reduction in edema of the hind paws.

Results are summarized as follows:

                  Table 1                                                          ______________________________________                                         Body Weight Gain                                                                             No. of                                                                               0       6       10 days                                    Compounds   mg/kg   rats    average                                            ______________________________________                                         Positive Control                                                                           --      8       202.0 195.9 194.6                                  4-n-butyl benzopheone                                                                      100     6       229.2 217.5 218.2                                    "         200     7       214.1 213.3 220.1                                  4-n-butyl-2'-fluoro-                                                                        50     8       222.6 223.0 232.0                                  benzophenone                                                                     "         100     10      211.8 205.8 214.4                                  Phenylbutazone                                                                              50     7       215.6 207.7 214.3                                  ______________________________________                                    

                  Table 2                                                          ______________________________________                                         Relative Change of Established Swelling                                        in Hind Paws                                                                                    Relative Volume                                                                Ratio of Swelling                                                              No. of 6       10 days                                        Compounds     mg/kg    rats     average                                        ______________________________________                                         Positive Control                                                                             --       8        1.43  1.42                                     4-n-butyl benzophenone                                                                       100      6        0.97  1.02                                       "           200      7        0.76  0.75                                     4-n-butyl-2'-fluoro-                                                           benzophenone   50      8        0.74  0.76                                       "           100      10       0.78  0.73                                     Phenylbutazone                                                                                50      7        0.75  0.75                                     ______________________________________                                    

No side effect considered to be related to the test compounds was seen during the study, while phenylbutazone caused the hemorrhage and the ulceration of stomach in most of the animals at dosage levels of 50 and 100 mg/kg/day. 

What is claimed is:
 1. An anti-inflammatory compound which comprises: a benzophenone compound having the formula: ##STR12## wherein R is n-butyl or n-amyl.
 2. A method of reducing chronic inflammation in a mammal, which comprises: administering to said mammal a therapeutically acceptable amount of the compound of claim
 1. 